Research reportConditioned fear stimuli reinstate cocaine-induced conditioned place preference
Introduction
One of the most troubling aspects of cocaine dependence in humans is the craving and relapse that occur for many years. Potentially important contributors to relapse are stressful life events. Several studies have reported that individuals exposed to higher levels of stress are more likely to undergo relapse to alcohol and other drugs [11], [17], [25].
The mechanism by which stress leads to reinstatement (relapse) of drug-seeking and drug-taking behavior remains to be elucidated. However, more recently, animal models of drug dependence have used self-administration and conditioned place preference procedures to examine the role of stress in reinstatement of drug-seeking behavior. Stewart and Shaham and coworkers (see [23] for review), as well as others, have demonstrated through extensive and elegant studies that stress produces robust reinstatement of cocaine [1], [6], heroin [21], nicotine [22] and alcohol [12] self-administration. Nearly all studies have used footshock stress as the stimulus to reinstate drug-seeking (lever-pressing) in animals previously extinguished for this behavior. Two recent reports using the conditioned place preference (CPP) procedure have also demonstrated that footshock reinstates morphine-induced place preference [14], [27].
The self-administration studies mentioned above demonstrated that a footshock stress produced clear reinstatement of lever pressing, but that a conditioned fear stress or a predatory odor presentation did not reinstate drug self-administration (see [23]). One possibility for differences in the ability to induce reinstatement by these stimuli is that activation of nociceptive pathways by footshock may be involved in producing the reinstatement. This does not seem likely, however, given that food-deprivation also induces reinstatement of drug self-administration [5], [24]. An alternative possibility is that, since conditioned fear behavior is manifest as an increase in freezing behavior in the rat, this response may interfere with the ability to lever-press on a test for reinstatement.
The present study examined whether a conditioned fear stress would reinstate cocaine conditioned place preference. Such findings may be of consequence to humans because they would suggest that stimuli previously associated with stressful events could precipitate relapse. For the studies described herein, it was reasoned that approach to the drug-paired chamber would be minimally impaired by a conditioned fear stimulus, as compared to active lever-pressing required in self-administration studies. Pilot studies in this laboratory indicated that a conditioned fear stimulus produced significant reinstatement of cocaine CPP in rats previously given the conditioned stimulus paired with footshock (PRD group). However, no comparison was conducted in rats given random presentations of footshock with the conditioned stimulus (RND group). Here we repeated the studies in the PRD group of rats and included a RND group to determine whether the ability of the conditioned fear stimulus would reinstate cocaine CPP to a greater extent in the PRD vs. RND group.
Section snippets
Materials and methods
Experiments were conducted according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and experimental protocols were approved by the University Animal Care and Use Committee. Male Sprague–Dawley rats weighing 260–280 g were supplied by Simonsen Laboratories (Gilroy, CA, USA). Rats were housed with food and water available ad libitum in constant temperature and humidity conditions on a 12 h light–dark cycle (light period 07.00 to 19.00 h).
The box used for
Results
The results in Fig. 1A–C show conditioned place preference behavior in RND and PRD groups trained and tested for reinstatement by the conditioned odor. Both groups demonstrated a significant place preference for the cocaine-paired side on the Cocaine Test (compared to day 0; P<0.0001 for both groups using a paired t-test). Fig. 1A shows that during extinction, rats did not reach the values for time spent on the cocaine-paired side as low as those demonstrated on day 0, the preconditioning day.
Discussion
These findings indicate that a conditioned odor or tone that has been previously paired with a footshock elicits reinstatement of cocaine CPP. Presentation of tone provided a robust stimulus for the reinstatement of cocaine CPP, in which rats spent nearly all of the 15 min test period in the cocaine-paired compartment, despite the observation that the freezing response declined after the first 5 min.
These results are in general agreement with several studies by Stewart and Shaham and coworkers
Acknowledgements
This work was supported by US Public Health Service grant DA 11787 (BAS).
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